Auto-injector

ABSTRACT

An auto-injector for administering a dose of a liquid medicament (M) is presented having a tubular chassis telescopable in an elongate chassis, a carrier subassembly comprising a tubular carrier slidably arranged partially inside the chassis and inside the case, where the carrier is adapted to contain a syringe with a hollow injection needle, a drive spring and a plunger for forwarding load of the drive spring to a stopper of the syringe, wherein the syringe is lockable for joint axial translation with the carrier. The auto-injector also has a control spring arranged around the carrier, a needle insertion control mechanism for coupling a proximal end of the control spring to either the carrier for advancing it for needle insertion or to the chassis, wherein the needle insertion control mechanism comprises a first collar biased by the control spring in a proximal direction (P), wherein at least one fifth clip is arranged on one of the chassis or the first collar initially abutting a block on the other of the chassis or the first collar.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a U.S. National Phase Application pursuant to35 U.S.C. §371 of International Application No. PCT/EP2012/052653 filedFeb. 16, 2012, which claims priority to European Patent Application No.11155046.3 filed Feb. 18, 2011. The entire disclosure contents of theseapplications are herewith incorporated by reference into the presentapplication.

TECHNICAL FIELD

The invention relates to an auto-injector for administering a dose of aliquid medicament.

BACKGROUND

Administering an injection is a process which presents a number of risksand challenges for users and healthcare professionals, both mental andphysical.

Injection devices (i.e. devices capable of delivering medicaments from amedication container) typically fall into two categories—manual devicesand auto-injectors.

In a manual device—the user must provide the mechanical energy to drivethe fluid through the needle. This is typically done by some form ofbutton/plunger that has to be continuously pressed by the user duringthe injection. There are numerous disadvantages to the user from thisapproach. If the user stops pressing the button/plunger then theinjection will also stop. This means that the user can deliver anunderdose if the device is not used properly (i.e. the plunger is notfully pressed to its end position). Injection forces may be too high forthe user, in particular if the patient is elderly or has dexterityproblems.

The extension of the button/plunger may be too great. Thus it can beinconvenient for the user to reach a fully extended button. Thecombination of injection force and button extension can causetrembling/shaking of the hand which in turn increases discomfort as theinserted needle moves.

Auto-injector devices aim to make self-administration of injectedtherapies easier for patients. Current therapies delivered by means ofself-administered injections include drugs for diabetes (both insulinand newer GLP-1 class drugs), migraine, hormone therapies,anticoagulants etc.

Auto-injectors are devices which completely or partially replaceactivities involved in parenteral drug delivery from standard syringes.These activities may include removal of a protective syringe cap,insertion of a needle into a patient's skin, injection of themedicament, removal of the needle, shielding of the needle andpreventing reuse of the device. This overcomes many of the disadvantagesof manual devices. Injection forces/button extension, hand-shaking andthe likelihood of delivering an incomplete dose are reduced. Triggeringmay be performed by numerous means, for example a trigger button or theaction of the needle reaching its injection depth. In some devices theenergy to deliver the fluid is provided by a spring.

US 2002/0095120 A1 discloses an automatic injection device whichautomatically injects a pre-measured quantity of fluid medicine when atension spring is released. The tension spring moves an ampoule and theinjection needle from a storage position to a deployed position when itis released. The content of the ampoule is thereafter expelled by thetension spring forcing a piston forward inside the ampoule. After thefluid medicine has been injected, torsion stored in the tension springis released and the injection needle is automatically retracted back toits original storage position.

High viscosity medicaments require high forces for expelling themthrough the relatively thin injection needle. To achieve these forcesstrong drive springs are needed. This can lead to a high impact felt bythe user when inserting the needle into the skin and to high forces feltby the user when triggering the injection.

SUMMARY

It is an object of the present invention to provide an improvedauto-injector.

The object is achieved by an auto-injector according to claim 1.

Preferred embodiments of the invention are given in the dependentclaims.

In the context of this specification the term proximal refers to thedirection pointing towards the patient during an injection while theterm distal refers to the opposite direction pointing away from thepatient. The term inwards refers to a radial direction pointing towardsa longitudinal axis of the auto-injector whereas the term outwardsrefers to the opposite direction radially pointing away from thelongitudinal axis.

According to the invention an auto-injector for administering a dose ofa liquid medicament comprises:

-   -   a tubular chassis telescopable in an elongate chassis,    -   a carrier subassembly comprising a tubular carrier slidably        arranged partially inside the chassis and inside the case, the        carrier adapted to contain a syringe with a hollow injection        needle, a drive spring and a plunger for forwarding load of the        drive spring to a stopper of the syringe, wherein the syringe is        lockable for joint axial translation with the carrier,    -   a control spring arranged around the carrier,    -   a needle insertion control mechanism for coupling a proximal end        of the control spring to either the carrier for advancing it for        needle insertion or to the chassis.

In the context of this specification the chassis is generally consideredas being fixed in position so motion of other components is describedrelative to the chassis unless otherwise stated.

The needle insertion control mechanism comprises a first collar biasedby the control spring in a proximal direction, wherein at least onefifth clip is arranged on one of the chassis or the first collarinitially abutting a block on the other of the chassis or the firstcollar, wherein a ramped engagement between the fifth clip and thecarrier is provided for outwardly deflecting the fifth clip ontranslation of the carrier in the proximal direction, wherein outwarddeflection of the fifth clip and translation of the carrier in theproximal direction is initially prevented by the case outwardly abuttingthe fifth clip, wherein the case is at least initially biased in thedistal direction, wherein the case is arranged to translate against thebias in the proximal direction relative to the chassis into an advancedposition, e.g. when the chassis is pressed against an injection site,thereby translating a second window in the case outwardly behind thefifth clip thus allowing outward deflection so as to decouple the fifthclip from the block and to allow the first collar to abut against thecarrier and advance it, e.g. for needle insertion, under load of thecontrol spring. Besides the switching of the control spring to thecarrier for advancing the needle the outward deflection of the fifthclip provides a detent. The detent serves for providing a resistiveforce which has to be overcome to advance the carrier in the proximaldirection for needle insertion. Once the user applies a force on thetrigger button which exceeds a pre-determined value the fifth clipreleases, initiating the injection cycle. If the pre-determined value isnot overcome the detent pushes the carrier and trigger button back intotheir prior position. This ensures that the auto-injector is always in adefined state, either triggered or not triggered, not half triggered bythe user hesitating.

The first collar may comprise a fourth clip for engaging a fourth rib onthe carrier for needle insertion. At least one of the fourth clip andfourth rib is ramped so as to outwardly deflect the fourth clip fordisengaging the fourth clip from the fourth rib under load of thecontrol spring, wherein outward deflection of the fourth clip isinitially prevented by the case, wherein the case is allowed totranslate from the advanced position in the distal direction driven bythe control spring when the auto-injector is lifted from the injectionsite thereby translating a sixth recess in the case outwardly behind thefourth clip thus allowing outward deflection so as to decouple the firstcollar from the carrier subsequently allowing the first collar to abutthe chassis. Decoupling the carrier from the proximal end of the controlspring allows for retracting the carrier and hence the needle into aneedle safe position. This may be achieved by a separate retractionspring or by the control spring which would require coupling the distalend of the control spring to the carrier. When a separate retractionspring is used the proximal end of the control spring does notnecessarily have to be switched to the chassis. Besides the switching ofthe control spring to the chassis for allowing needle retraction, theoutward deflection of the fourth clip provides a detent. The detentserves for providing a resistive force resisting translation of thecarrier in the distal direction relative to the chassis for keeping thecarrier in a defined position in a transitional state with both ends ofthe control spring decoupled from the carrier. This transitional statemay be required for retracting the needle on removal from the injectionsite. As the carrier is biased against the injection site by the controlspring before removal from the injection site it has to be decoupledfrom the proximal end of the control spring and coupled to the distalend for retraction. The sequencing of this switching is critical asretraction will fail if both ends of the control spring are attached tothe carrier at the same time. This is overcome by separating theswitching of the ends by a significant displacement of the case, whichmoves in the distal direction relative to the chassis on removal of theinjection site under load of the control spring. As the switching of thedistal end of the control spring to the carrier depends on the relativeposition of the case to the carrier the carrier has to be fixed in thetransitional state which is achieved by the detent provided by thefourth clip.

The auto-injector may furthermore comprise:

-   -   a trigger button arranged distally or laterally in or on the        case,    -   a plunger release mechanism arranged for releasing the plunger        for injection when the carrier has at least almost reached an        injection depth during needle insertion,    -   a syringe retraction control mechanism arranged for coupling a        distal end of the control spring to either the carrier for        needle retraction or to the case otherwise.

The carrier subassembly with the integrated drive spring allows foremploying a strong drive spring without any impact on the user whentriggering the auto-injector or during needle insertion since theseactions are achieved or opposed by the control spring which can bespecified considerably weaker than the drive spring. This allows fordelivering highly viscous medicaments.

There are a number of significant benefits of separating the functionsbetween the drive spring and the control spring in this way. Theauto-injector is always needle safe, i.e. the needle can be retractedbefore the injection is complete. The reliability of the auto-injectoris improved as the components for needle advance and retraction are notloaded by the high impact of a freely expanding high force drive spring.The auto-injector is well suited to serve as a platform as the drivespring can be swapped to deliver different viscosity drugs withoutaffecting the insertion or retraction functions. This is particularlyadvantageous for high viscosity fluids.

Releasing the drive spring upon the needle reaching an injection depthavoids a so called wet injection, i.e. medicament leaking out of theneedle which is a problem in conventional art auto-injectors, where bothneedle insertion and injection are achieved by pushing on the stopper.The auto-injector solves the wet injection problem by the separatesprings for translation of the carrier and for drug delivery.

The auto-injector has a particularly low part count compared to mostconventional auto-injectors thus reducing manufacturing costs. Thearrangement with separate control spring and drive spring for fluidinjection allows for using one design for different viscosity liquids byjust changing the drive spring, and for different volumes just bychanging the length of the plunger. This is an advantage overconventional art designs where the main spring also powers needleinsertion and/or retraction.

In an initial as delivered state of the auto-injector the proximal endof the control spring is coupled to the chassis by the needle insertioncontrol mechanism while the distal end is coupled to the case by thesyringe retraction control mechanism, release of the drive spring isprevented by the plunger release mechanism, decoupling of the chassisfrom the carrier is prevented by the needle insertion control mechanism.

In order to trigger an injection the auto-injector has to be pressedagainst the injection site, e.g. a patient's skin. The user, e.g. thepatient or a caregiver, grabs the case with their whole hand and pushesthe chassis protruding from the proximal end against the injection site.

When pushed against the injection site, the case translates in theproximal direction relative to the chassis against the force of thecontrol spring. When the case has at least almost reached an advancedposition the needle insertion control mechanism is unlocked therebyallowing translation of the carrier relative to the chassis.

The carrier can now be translated, preferably manually by depressing thetrigger button forcing the carrier in the proximal direction. Thecarrier translates in the proximal direction relative to the case and tothe chassis thereby switching the needle insertion control mechanismdepending on the relative position of the carrier in the chassis so asto decouple the proximal end of the control spring from the chassis andcouple it to the carrier, thereby releasing the control spring foradvancing the carrier for needle insertion.

As the needle translated with the carrier subassembly at least almostreaches an injection depth the drive spring is released by the plungerrelease mechanism thereby allowing the drive spring to advance theplunger and the stopper for at least partially delivering themedicament. The release of the drive spring is preferably triggered bythe carrier reaching a predefined relative position within the case.

If the auto-injector is removed from the injection site after thestopper has bottomed out in the syringe or mid injection, the case istranslated in the distal direction under load of the control springrelative to the carrier subassembly.

As the case reaches a defined position relative to the carrier duringthat motion the proximal end of the control spring is decoupled from thecarrier and coupled to the chassis by the needle insertion controlmechanism. Furthermore the distal end of the control spring is decoupledfrom the trigger sleeve and coupled to the carrier by the syringeretraction control mechanism. As the control spring now pushes againstthe chassis in the proximal direction and against the carrier in thedistal direction the carrier subassembly is retracted into the chassisinto a needle safe position by the control spring.

The plunger release mechanism may comprise at least one resilient arm onthe carrier arranged to be in a ramped engagement to the plunger so asto disengage them under load of the drive spring, wherein a pegprotrudes from a distal end face of the trigger button in the proximaldirection in a manner to support the resilient arm preventingdisengagement of the carrier from the plunger and thus release of thedrive spring when the carrier is in a distal position. The triggerbutton is arranged to remain in position relative to the case when thecarrier is translated for advancing the needle. That means, the triggerbutton, initially coupled to the carrier, pushes the carrier in theproximal direction when depressed. As soon as the control spring takesover further advancing the carrier the trigger button may abut the caseand decouple from the carrier, staying in position as the carrier moveson. Hence the resilient arm is pulled away from the peg thus allowingdeflection of the resilient arm due to the ramped engagement under loadof the drive spring for disengaging the plunger from the carrier andreleasing the drive spring for drug delivery when the carrier hasreached a predefined position during needle advancement.

In an alternative plunger release mechanism the plunger in an initialstate is locked to the carrier by a ramped engagement to the carrier andby being prevented from rotating out of this ramped engagement dependingon a relative longitudinal position of the carrier in the case, whereinthe plunger is arranged to be released for rotating out of the rampedengagement upon the needle reaching at least nearly a predefinedinjection depth on translation of the carrier in the proximal directionfor advancing the needle beyond a proximal end of the auto-injector.This plunger release mechanism is a particularly reliable and efficientway of triggering injection of the medicament upon the needle reachingthe injection depth.

In one embodiment of the invention the carrier has a longitudinalaperture, wherein an outward protrusion is arranged on the plunger in amanner to engage a face on the carrier in the aperture, wherein at leastone of the outward protrusion or the face on the carrier is ramped so asto force the plunger to rotate when translated, wherein an inwardlongitudinal rib connected to the case inwardly protrudes into thelongitudinal aperture in a manner to prevent disengagement of theoutward protrusion from the face on the carrier prior to translation ofthe carrier for advancing the needle and wherein the outward protrusioncomes clear of the inward longitudinal rib on translation of the carrierfor advancing the needle so as to rotate past a proximal end of theinward longitudinal rib due to its ramped engagement to the carrierunder load of the drive spring.

The inward longitudinal rib may be arranged on a second collar arrangedin the case and initially locked to the case for joint axialtranslation, the second collar being part of a syringe retractioncontrol mechanism, wherein the syringe retraction control mechanism isarranged to disengage from the case and engage to the carrier when thecase is moved in the distal direction from a position with the needle inthe injection depth, wherein a control spring is arranged in the casearound the carrier, the control spring acting with its distal endagainst the second collar so as to bias the case or the carrier in thedistal direction. The proximal end of the control spring may act againsta first collar.

In one embodiment the inward longitudinal rib may be arranged on asecond collar arranged in the case and initially locked to the case forjoint axial translation, the second collar being part of a syringerefraction control mechanism, wherein the syringe retraction controlmechanism is arranged to disengage from the case and engage to thecarrier when the case is moved in the distal direction relative to thecarrier with the needle beyond a proximal end of the auto-injector,wherein a control spring is arranged in the case around the carrier, thecontrol spring acting with its distal end against the second collar soas to bias the case or the carrier in the distal direction. The proximalend of the control spring may act against a first collar. The needlebeing beyond a proximal end of the auto-injector may relate to aposition of the needle in the injection site, e.g. it may relate to aposition at injection depth.

When the auto-injector or the syringe is assembled a protective needlesheath may be attached to the needle for keeping the needle sterile andpreventing both, damage to the needle during assembly and handling andaccess of a user to the needle for avoiding finger stick injuries.Removal of the protective needle sheath prior to an injection usuallyrequires a relatively high force for pulling the protective needlesheath off the needle and needle hub in the proximal direction. In orderto maintain pre injection needle safety and prevent exposure of theneedle translation of the syringe in the proximal direction due to thisforce has to be avoided. This is achieved by the carrier initially beingin the ramped engagement to the chassis by the fifth clip trying todeflect it and the fifth clip being prevented from deflecting by thecase. In order to ensure that the case is not moved in the proximaldirection unlocking the fifth clip before the protective needle sheathis removed a cap may be attached to the proximal end of the case so asto make the chassis inaccessible before the cap is removed. The cappreferably engages the protective needle sheath by means of a barb in amanner to remove the protective needle sheath when the cap is beingpulled off the auto-injector. In order to facilitate removal of the capit may have a profiled surface mating with a surface on the case so thatthe cap is pulled off when rotated. The barb may be connected to the capin a manner allowing them to rotate independently so as to avoid torqueon the protective needle sheath when the cap is rotated in order not todistort the needle inside the protective needle sheath.

The distally arranged trigger button may be at least initially coupledto the carrier, wherein the case is arranged to abut the trigger buttonin the initial state preventing depression of the trigger button. Ontranslation of the case into the advanced position, e.g. when thechassis is being pressed against the injection site, the trigger buttonremains coupled to the carrier thus emerging from the case which hasbeen moved relative to the chassis, carrier and trigger button so as toallow depression of the trigger button, e.g. for starting an injectioncycle. Thus a sequence of operation is defined for the auto-injector tobe actuated, first pressing it against the injection site and then topush the trigger button. This reduces the risk of finger stick injuriesparticularly if the user were to be confused which end of theauto-injector to apply against their skin. Without a sequence the userwould risk inserting the needle into their thumb which is significantlyless probable with the forced sequence.

The syringe retraction control mechanism may comprise a second collarbearing against the distal end of the control spring and having aresilient proximal beam with a second beam head having an inward boss.The second beam head is arranged to be in a ramped engagement with asecond case detent in the case in a manner ramping the second beam headin the inward direction under load of the control spring in the distaldirection. The inward boss is arranged to inwardly abut the carrier forpreventing inward deflection of the second beam head and keep the secondcollar locked to the case. A third recess is arranged in the carrier forallowing the inward boss to be inwardly deflected on translation of thecase in the distal direction relative to the carrier, e.g. on removal ofthe auto-injector from the injection site.

In an alternative embodiment the trigger button may be arrangeddistally, wherein the case is arranged as a wrap-over sleeve triggerhaving a closed distal end face covering the trigger button. In aninitial state a clearance is provided between the distal end face of thesleeve trigger and the trigger button allowing for some travel of thesleeve trigger against the bias of the control spring in the proximaldirection in a first phase before abutting the trigger button. As soonas the sleeve trigger has contacted the trigger button the triggerbutton is pushed by the sleeve trigger on further translation in asecond phase. This embodiment allows for keeping the majority of thecomponents of the auto-injector while only the described features needmodification allowing to customize a platform device to particularrequirements. An auto-injector with a sleeve trigger is particularlywell suited for people with dexterity problems since, as opposed toconventional art auto-injectors, triggering does not require operationof small buttons by single fingers. Instead, the whole hand is used.

Retraction of the needle requires the user to lift the auto-injector farenough from the injection site to allow the case or sleeve trigger totranslate back in the distal direction to switch the control spring. Asit may be difficult for the user to know if the injection is finished ornot a releasable noise component may be provided, capable of, uponrelease, generating an audible and/or tactile feedback to the user,wherein the noise component is arranged to be released when the plungerreaches a position relative to the syringe in which the stopper islocated in proximity of a proximal end of the syringe, i.e. when theinjection is at least almost finished. The released noise component thenmay impact on a housing component, such as the case, sleeve trigger ortrigger button indicating the end of the injection. Impacting a directlyaccessible component allows for high perceptibility of the noise anddirect access to the user's hand or finger for generating the tactilefeedback. Preferably the noise component may impact the trigger buttonwhich may be shaped as a drum for providing a loud noise.

The needle insertion depth is preferably defined by the carrier relativeto the chassis not relative to the case, so if the user flinches orfails to hold the auto-injector hard against the injection site, onlythe case will move in the distal direction while the injection depthremains constant. As long as this case motion does not exceed a setdistance the case does not yet switch the control spring for needleretraction.

A visual use indicator may be provided for facilitating distinctionbetween a used and an unused auto-injector, the visual use indicatorcomprising at least one indicator window in the case, wherein a part ofthe chassis is arranged to be located behind the indicator window whenthe case is in its distal position biased by the control spring, whereina tab on the first collar is located outwardly from the part of thechassis after the collar has been translated in the proximal directionduring needle insertion, wherein the tab and the part of the chassisexhibit a visually distinctive feature, e.g. different colours orpatterns. The colours may be applied to the tab and the part of thechassis or the tab and the chassis may be made of differently colouredmaterials.

In another embodiment the trigger button may be initially coupled to thecase in a manner to protrude distally from the case and interlocked tothe chassis in a manner preventing the trigger button from disengagingthe case and thus preventing actuation of the trigger button in aninitial position, wherein the case is arranged to translate in theproximal direction against the bias relative to the chassis when thechassis is pressed against an injection site thereby also translatingthe trigger button releasing the interlock to the chassis so as to allowactuation of the trigger button, wherein the trigger button is arrangedto lock in a more proximal position on actuation.

Thus the sequence of operation is defined for the auto-injector to beactuated, first pressing it against the injection site and then to pushthe trigger button.

The trigger button locking in a more proximal than the initial positionindicates that the auto-injector has already been used so the user iskept from attempting to use it again and reminded to purchase a new one.

The auto-injector may be operated by a number of key mechanicaloperations:

-   -   The case is advanced relative to the chassis compressing the        control spring giving the user the impression of depressing a        skin interlock sleeve. All other components remain in the same        place during case advance resulting in the trigger button        appearing from the distal end of the case.    -   The user pushes the trigger button which can now be operated.        Button depression directly moves the carrier and hence the drive        sub-assembly in the proximal direction a set distance until the        control spring takes over via the first collar and inserts the        needle into the injection site.    -   The trigger button stops on the distal end of the case as the        carrier continues translating in the proximal direction. The        motion of the carrier relative to the trigger button is used to        release the drive spring just before full insertion depth is        reached, e.g. by pulling a peg on the trigger button out of the        carrier thus allowing the plunger to move. The drive spring        drives the plunger down the syringe barrel expelling the        medicament.    -   The noise mechanism is released when the plunger is near the end        of travel shortly before the stopper bottoms out in the syringe,        indicating the end of injection to the user.    -   The needle remains fully inserted until the user moves the case        back a set distance at which point the second collar decouples        from the case and couples to the carrier while the first collar        decouples from the carrier and couples to the chassis thus        allowing the control spring to retract the carrier and hence the        needle.

The auto-injector may preferably be used for subcutaneous orintra-muscular injection, particularly for delivering one of ananalgetic, an anticoagulant, insulin, an insulin derivate, heparin,Lovenox, a vaccine, a growth hormone, a peptide hormone, a proteine,antibodies and complex carbohydrates.

The term “medicament”, as used herein, means a pharmaceuticalformulation containing at least one pharmaceutically active compound,

wherein in one embodiment the pharmaceutically active compound has amolecular weight up to 1500 Da and/or is a peptide, a proteine, apolysaccharide, a vaccine, a DNA, a RNA, a antibody, an enzyme, anantibody, a hormone or an oligonucleotide, or a mixture of theabove-mentioned pharmaceutically active compound,

wherein in a further embodiment the pharmaceutically active compound isuseful for the treatment and/or prophylaxis of diabetes mellitus orcomplications associated with diabetes mellitus such as diabeticretinopathy, thromboembolism disorders such as deep vein or pulmonarythromboembolism, acute coronary syndrome (ACS), angina, myocardialinfarction, cancer, macular degeneration, inflammation, hay fever,atherosclerosis and/or rheumatoid arthritis,

wherein in a further embodiment the pharmaceutically active compoundcomprises at least one peptide for the treatment and/or prophylaxis ofdiabetes mellitus or complications associated with diabetes mellitussuch as diabetic retinopathy,

wherein in a further embodiment the pharmaceutically active compoundcomprises at least one human insulin or a human insulin analogue orderivative, glucagon-like peptide (GLP-1) or an analogue or derivativethereof, or exedin-3 or exedin-4 or an analogue or derivative ofexedin-3 or exedin-4.

Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) humaninsulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) humaninsulin; Asp(B28) human insulin; human insulin, wherein proline inposition B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein inposition B29 Lys may be replaced by Pro; Ala(B26) human insulin;Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) humaninsulin.

Insulin derivates are for example B29-N-myristoyl-des(B30) humaninsulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl humaninsulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin;B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30human insulin; B29-N-(N-palmitoyl-Y-glutamyl)-des(B30) human insulin;B29-N-(N-lithocholyl-Y-glutamyl)-des(B30) human insulin;B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin andB29-N-(ω-carboxyheptadecanoyl) human insulin.

Exendin-4 for example means Exendin-4(1-39), a peptide of the sequenceH-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.

Exendin-4 derivatives are for example selected from the following listof compounds:

-   H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,-   H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2,-   des Pro36 [Asp28] Exendin-4(1-39),-   des Pro36 [IsoAsp28] Exendin-4(1-39),-   des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),-   des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),-   des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),-   des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),-   des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),-   des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or-   des Pro36 [Asp28] Exendin-4(1-39),-   des Pro36 [IsoAsp28] Exendin-4(1-39),-   des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),-   des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),-   des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),-   des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),-   des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),-   des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39),    wherein the group -Lys6—NH2 may be bound to the C-terminus of the    Exendin-4 derivative;    or an Exendin-4 derivative of the sequence-   H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6—NH2,-   des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,-   H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2,-   H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2,-   des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6—NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6—NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28]    Exendin-4(1-39)-(Lys)6—NH2,-   H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6—NH2,-   H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)—NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-NH2,-   des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6—NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6—NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6—NH2,-   H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6—NH2,-   des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2,-   H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-NH2,-   des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-(Lys)6—NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-(Lys)6—NH2,-   H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-(Lys)6—NH2,-   H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(1-39)-Lys6—NH2,-   H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25]    Exendin-4(1-39)-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(1-39)—NH2,-   des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6—NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(S1-39)-(Lys)6-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6—NH2;    or a pharmaceutically acceptable salt or solvate of any one of the    afore-mentioned Exedin-4 derivative.

Hormones are for example hypophysis hormones or hypothalamus hormones orregulatory active peptides and their antagonists as listed in RoteListe, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin,Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin),Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin,Buserelin, Nafarelin, Goserelin.

A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid,a heparin, a low molecular weight heparin or an ultra low molecularweight heparin or a derivative thereof, or a sulphated, e.g. apoly-sulphated form of the above-mentioned polysaccharides, and/or apharmaceutically acceptable salt thereof. An example of apharmaceutically acceptable salt of a poly-sulphated low molecularweight heparin is enoxaparin sodium.

Pharmaceutically acceptable salts are for example acid addition saltsand basic salts. Acid addition salts are e.g. HCl or HBr salts. Basicsalts are e.g. salts having a cation selected from alkali or alkaline,e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), whereinR1 to R4 independently of each other mean: hydrogen, an optionallysubstituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenylgroup, an optionally substituted C6-C10-aryl group, or an optionallysubstituted C6-C10-heteroaryl group. Further examples ofpharmaceutically acceptable salts are described in “Remington'sPharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), MarkPublishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia ofPharmaceutical Technology.

Pharmaceutically acceptable solvates are for example hydrates.

The drive spring and control spring may be compression springs. However,they may likewise be any kind of stored energy means such as torsionsprings, gas springs etc.

Further scope of applicability of the present invention will becomeapparent from the detailed description given hereinafter. However, itshould be understood that the detailed description and specificexamples, while indicating preferred embodiments of the invention, aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will become more fully understood from thedetailed description given hereinbelow and the accompanying drawingswhich are given by way of illustration only, and thus, are not limitiveof the present invention, and wherein:

FIG. 1 shows two longitudinal sections of an auto-injector in differentsection planes in a state prior to use,

FIG. 2 shows two longitudinal sections of the auto-injector afterremoval of a cap and a protective needle sheath,

FIG. 3 shows two longitudinal sections of the auto-injector with aproximal end pressed against an injection site,

FIG. 4 shows two longitudinal sections of the auto-injector with atrigger button depressed,

FIG. 5 shows two longitudinal sections of the auto-injector duringneedle insertion into the injection site,

FIG. 6 shows two longitudinal sections of the auto-injector with theneedle fully inserted,

FIG. 7 shows two longitudinal sections of the auto-injector duringinjection near the end of dose,

FIG. 8 shows two longitudinal sections of the auto-injector at the endof dose,

FIG. 9 shows two longitudinal sections of the auto-injector removed fromthe injection site,

FIG. 10 shows two longitudinal sections of the auto-injector with theneedle retracted into a needle safe position,

FIG. 11 shows schematic views of a detent mechanism for controllingmovement of a carrier relative to a chassis of the auto-injector in fourdifferent states,

FIG. 12 shows schematic views of a needle insertion control mechanismfor controlling movement of a first collar in six different states,

FIG. 13 shows schematic views of a syringe retraction control mechanismin three different states

FIG. 14 shows schematic views of a noise release mechanism for audiblyindicating the end of injection in three different states,

FIG. 15 shows schematic views of a plunger release mechanism in threedifferent states,

FIG. 16 shows schematic views of a button release mechanism in threedifferent states,

FIG. 17 is an isometric view of an alternative embodiment of the plungerrelease mechanism,

FIG. 18 is a longitudinal section of an alternative embodiment of thebutton release mechanism,

FIG. 19 shows longitudinal sections of an alternative embodiment of thedetent mechanism,

FIG. 20 is a longitudinal section of a third embodiment of the detentmechanism,

FIG. 21 is a longitudinal section of an alternative embodiment of thenoise release mechanism,

FIG. 22 shows longitudinal sections of an alternative embodiment of theneedle insertion control mechanism, also arranged to perform thefunction of the detent mechanism on needle retraction and needleinsertion,

FIG. 23 is an isometric view of the needle insertion control mechanismof FIG. 22,

FIG. 24 shows longitudinal sections of a third embodiment of the needleinsertion control mechanism, also arranged to perform the functions ofthe detent mechanism,

FIG. 25 is an isometric view of the needle insertion control mechanismof FIG. 24,

FIG. 26 shows longitudinal sections of a third embodiment of the noiserelease mechanism, and

FIG. 27 is another embodiment of the auto-injector having a wrap-oversleeve trigger instead of a trigger button.

Corresponding parts are marked with the same reference symbols in allfigures.

DETAILED DESCRIPTION

A ramped engagement in the terminology of this specification is anengagement between two components with at least one of them having aramp for engaging the other component in such a manner that one of thecomponents is flexed aside when the components are axially pushedagainst each other provided this component is not prevented from flexingaside.

FIGS. 1 a and 1 b show two longitudinal sections of an auto-injector 1in different section planes, the different section planes approximately90° rotated to each other, wherein the auto-injector 1 is in an initialstate prior to starting an injection. The auto-injector 1 comprises achassis 2. In the following the chassis 2 is generally considered asbeing fixed in position so motion of other components is describedrelative to the chassis 2. A syringe 3, e.g. a Hypak syringe, with ahollow injection needle 4 is arranged in a proximal part of theauto-injector 1. When the auto-injector 1 or the syringe 3 is assembleda protective needle sheath 5 is attached to the needle 4. A stopper 6 isarranged for sealing the syringe 3 distally and for displacing a liquidmedicament M through the hollow needle 4. The syringe 3 is held in atubular carrier 7 and supported at its proximal end therein. The carrier7 is slidably arranged in the chassis 2.

A drive spring 8 in the shape of a compression spring is arranged in adistal part of the carrier 7. A plunger 9 serves for forwarding theforce of the drive spring 8 to the stopper 6.

The drive spring 8 is loaded between a distal carrier end face 10 of thecarrier 7 and a thrust face 11 arranged distally on the plunger 9.

The carrier 7 is a key element housing the syringe 3, the drive spring 8and the plunger 9, which are the components required to eject themedicament M from the syringe 3. These components can therefore bereferred to as a drive sub-assembly.

The chassis 2 and the carrier 7 are arranged within a tubular case 12. Atrigger button 13 is arranged at a distal end of the case 12. In aplunger release mechanism 27 a peg 14 protrudes from a distal end faceof the trigger button 13 in the proximal direction P between tworesilient arms 15 originating from the distal carrier end face 10 thuspreventing them from flexing towards each other in an initial state Aillustrated in FIG. 15A. In FIG. 15A only one of the resilient arms 15is shown to illustrate the principle. Outwardly the resilient arms 15are caught in respective first recesses 16 in a distal plunger sleeve 17attached distally to the thrust face 11 and arranged inside the drivespring 8. The engagement of the resilient arms 15 in the first recesses16 prevents axial translation of the plunger 9 relative to the carrier7. The resilient arms 15 are ramped in a manner to flex them inwards onrelative motion between the plunger 9 and the carrier 7 under load ofthe drive spring 8, which is prevented by the peg 14 in the initialstate A.

The carrier 7 is locked to the chassis 2 for preventing relativetranslation by a detent mechanism 18 illustrated in more detail in FIGS.11A to 11D.

The trigger button 13 is initially engaged to the case 12 by a buttonrelease mechanism 26 and cannot be depressed. The button releasemechanism 26 is illustrated in detail in FIGS. 16A to 16C. Referring nowto FIG. 16A the button release mechanism 26 comprises a resilientproximal beam 13.1 on the trigger button 13, the proximal beam 13.1having an outward first ramp 13.2 and an inward second ramp 13.3. In aninitial state A illustrated in FIG. 16A the outward first ramp 13.2 isengaged in a ramped first case detent 12.1 preventing the trigger button13 from moving out of the distal end D. The trigger button 13 proximallyabuts both the case 12 and the carrier 7 hence being prevented frombeing depressed in the proximal direction P.

Referring again to FIGS. 1A and 1B a control spring 19 in the shape ofanother compression spring is arranged around the carrier 7 and actsbetween a proximal first collar 20 and a distal second collar 21. Thecontrol spring 19 is used to move the carrier 7 and hence the drivesub-assembly in the proximal direction P for needle insertion or in thedistal direction D for needle retraction.

In the state as delivered as shown in FIGS. 1 a and 1 b a cap 22 isattached to the proximal end of the case 12 and the protective needlesheath 5 is still in place over the needle 4 and the needle hub. Aninner sleeve 22.1 of the cap 22 is arranged inside the chassis 2 andover the protective needle sheath 5. In the inner sleeve 22.1 a barb 23is attached. The barb 23 is engaged to the protective needle sheath 5for joint axial translation.

A sequence of operation of the auto-injector 1 is as follows:

A user pulls the cap 22 from the proximal end of the case 12. The barb23 joins the protective needle sheath 5 to the cap 22. Hence, theprotective needle sheath 5 is also removed on removal of the cap 22.FIGS. 2 a and 2 b show the auto-injector 1 with the cap 22 and needlesheath 5 removed. The carrier 7 and syringe 3 are prevented from movingin the proximal direction P by the detent mechanism 18 being in a stateA as in FIG. 11A. Referring now to FIG. 11A, the detent mechanism 18comprises a resilient beam 2.1 on the chassis 2 with an inwardlyprotruding first beam head 2.2. The first beam head 2.2 has a proximalthird ramp 2.3. The detent mechanism 18 further comprises a rhomboidramp member 7.1 on the carrier 7 having a proximal fourth ramp 7.2 and adistal fifth ramp 7.3. In state A a rounded off distal side of the firstbeam head 2.2 abuts the ramp member 7.1 in the distal direction Dresisting movement of the carrier 7 in the proximal direction P relativeto the chassis 2. A rib on the case 12 is provided for preventingoutward deflection of the resilient beam 2.1 thereby also preventingmotion of the carrier 7 relative to the chassis 2.

Referring again to FIGS. 2A and 2B the user grabs the case 12 and placesthe chassis 2 protruding from the case 12 at the proximal end P againstan injection site, e.g. a patient's skin. As the auto-injector 1 ispressed against the injection site the case 12 translates in theproximal direction P relative to the chassis 2 into an advanced positionas illustrated in FIGS. 3A and 3B. The second collar 21 is locked to thecase 12 and is moved with the case 12 relative to the chassis 2 andrelative to nearly all other components of the auto-injector 1 thusslightly compressing the control spring 19 against the first collar 20which is prevented from moving in the proximal direction P by thechassis 2 due to a needle insertion control mechanism 24 being in astate A illustrated in detail in FIG. 12A. Referring now to FIG. 12A, aresilient member in the shape of an arrowhead 20.1 is proximallyarranged on the first collar 20. The first collar 20 with the arrowhead20.1 is being forced in the proximal direction P under load of thecompressed control spring 19. An outward sixth ramp 20.2 on thearrowhead 20.1 interacts with a second distal seventh ramp 2.4 on thechassis 2 ramping the arrowhead 20.1 in an inward direction I which isprevented by the arrowhead 20.1 inwardly abutting the carrier 7. Hence,the first collar 20 cannot translate in the proximal direction P.

Referring again to FIGS. 3A and 3B the second collar 21 is locked to thecase due to a syringe refraction control mechanism 25 being in a state Aillustrated in detail in FIG. 13A. Referring now to FIG. 13A, thesyringe retraction control mechanism 25 comprises a resilient proximalbeam 21.1 on the second collar 21, the proximal beam 21.1 having asecond beam head 21.2 having an inward boss 21.3 and a distal outwardeighth ramp 21.4. The distal outward eighth ramp 21.4 is engaged in aramped second case detent 12.2 in a manner ramping the second beam head21.1 in the inward direction I with the second collar 21 under load ofthe control spring 19 in the distal direction D which is prevented bythe inward boss 21.3 inwardly abutting the carrier 7.

Referring again to FIGS. 3A and 3B, if the user was to move the case 12away from the injection site, the control spring 19 expands returningthe auto-injector 1 to the initial condition after removal of the cap 22as illustrated in FIGS. 2A and 2B.

In the state as in FIGS. 3A and 3B the carrier 7 continues to beprevented from moving in the proximal direction P by the detentmechanism 18, however with the case 12 in its advanced position thedetent mechanism 18 is unlocked as the rib on the case 12 has also movedand no longer prevents outward deflection of the resilient beam 2.1.Movement of the case 12 relative to the carrier 7, which is locked tothe chassis 2 by the detent mechanism 18, causes the button releasemechanism 26 to switch to a state B illustrated in FIG. 16B. The triggerbutton 13 cannot translate with the case 12 in the proximal direction Pas it is abutted against the carrier 7. The ramp on the first casedetent 12.1 interacts with the outward first ramp 13.2 on the proximalbeam 13.1 on the trigger button 13 deflecting the proximal beam 13.1 inthe inward direction I thus engaging the inward second ramp 13.3 on theproximal beam 13.1 in a ramped carrier detent 7.4 arranged in thecarrier 7. As the case 12 is translated further in the proximaldirection P it supports the proximal beam 13.1 outwardly thus lockingthe trigger button 13 to the carrier 7. The trigger button 13 nowprotrudes from the distal end D of the chassis 12 and is ready to bepressed.

In the state as in FIGS. 3A and 3B the user depresses the trigger button13 in the proximal direction P. As the trigger button 13 abuts againstthe carrier 7 the carrier 7 is pushing in the proximal direction Pagainst the chassis 2, the carrier 7 and the chassis 2 interacting inthe detent mechanism 18. The force exerted by the user pressing thetrigger button 13 is resolved through the chassis 2 onto the injectionsite, not between the trigger button 13 and the case 12. The detentmechanism 18 provides a resistive force when the user pushes the triggerbutton 13. Once the user applies a force which exceeds a pre-determinedvalue the detent mechanism 18 releases, initiating the injection cycle.Referring now to FIG. 11B showing the detent mechanism 18 in a state B,the resilient beam 2.1 on the chassis 2 begins to bow under load fromthe rhomboid ramp member 7.1 on the carrier 7, storing elastic energy.Despite the proximal fourth ramp 7.2 on the ramp member 7.1 frictionbetween the contacting faces of the first beam head 2.2 and the proximalfourth ramp 7.2 prevents movement of the first beam head 2.2 in theoutward direction O until the straightening force in the resilientlydeformed beam 2.1 is sufficiently large to overcome it. At this pointthe resilient beam 2.1 is deflected in the outward direction O movingout of the way of the carrier 7 thus allowing the carrier 7 to translatein the proximal direction P. When the carrier 7 travels sufficiently farin the proximal direction P the rhomboid ramp member 7.1 on the carrier7 passes under the first beam head 2.2 thus allowing it to relax andmove back in the inward direction I distally behind the rhomboid rampmember 7.1 in a state C illustrated in FIG. 11C at the same timeconstraining translation of the carrier 7 in the distal direction Drelative to the chassis 2.

Once the carrier 7 slides far enough in the proximal direction Prelative to the first collar 20 the needle insertion control mechanism24 is switched to a state B as illustrated in FIG. 12B. In FIG. 12B thecarrier 7 has been translated in the proximal direction P in such amanner that the arrowhead 20.1 on the first collar 20 is no longerinwardly supported. This may be achieved by a second recess 7.5 in thecarrier 7. The arrowhead 20.1 is now deflected in the inward direction Iinto the second recess 7.5 under load of the control spring 19 arrivingat a state C as illustrated in FIG. 12C. The first collar 20 is nowdecoupled from the chassis 2. Instead, the arrowhead 20.1 couples thefirst collar 20 to the carrier 7 by an inward ninth ramp 20.3 engaging adistal tenth ramp 7.6 on the carrier 7 at the proximal end of the secondrecess 7.5. Hence, the control spring 19 continues moving the carrier 7in the proximal direction P from this point. Whilst the user advancesthe needle 4 by a proportion of its travel, the control spring 19 takesover insertion before the needle 4 protrudes from the proximal end P.Therefore the user experience is that of pressing a button, rather thanmanually inserting a needle.

The detent mechanism 18 relies on the user applying a force rather thana displacement. Once the force applied exceeds the force required toswitch the detent the user will push the trigger button 13 fully,ensuring that the first collar 20 will always switch. If the user failsto pass the detent, the trigger button 13 returns to its unused stateready for use as illustrated in FIGS. 3A and 3B. This feature avoids theauto-injector 1 arriving in an undefined state.

FIGS. 4A and 4B show the auto-injector 1 with the trigger button 13depressed sufficiently for the control spring 19 to couple on to thecarrier 7 and continue moving the carrier 7 forwards, but not yetabutting the case 12.

The carrier 7 coupled to the first collar 20 is translated in theproximal direction P driven by the control spring 19. As the syringe 3is arranged for joint axial translation with the carrier 3 the syringe 3and needle 4 are also translated resulting in the needle 4 protrudingfrom the proximal end P and being inserted into the injection site. Thetrigger button 13 returns to its initial position relative to the case12 and latches back to the case 12 from the carrier 7 as in state

A in FIG. 16 A. The carrier 7 translates further in the proximaldirection P preventing inward deflection of the proximal beam 13.1 sothe outward first ramp 13.2 cannot disengage from the first case detent12.1.

Immediately prior to the needle 4 reaching full insertion depth asillustrated in FIGS. 5A and 5B the peg 14 on the trigger button 13 iscompletely pulled out from between the resilient arms 15 on the carrier7. Hence, the plunger release mechanism 27 arrives in a state B shown inFIG. 15B with the resilient arms 15 no longer inwardly supported by thepeg 14. Due to the ramped engagement of the resilient arms 15 in thefirst recess 16 they are deflected in the inward direction I under loadof the drive spring 8 arriving in a state B illustrated in FIG. 15C.Hence, the plunger 9 is released from the carrier 7 and driven in theproximal direction P by the drive spring 8, ready to inject themedicament M. The force to pull the peg 14 out from between theresilient arms 15 is provided by the control spring 19 while the forcerequired to deflect the resilient arms 15 out of engagement to theplunger 9 is provided by the drive spring 8.

While the plunger 9 moves and closes a gap to the stopper 6 the movementof the carrier 7 in the proximal direction P is completed by the controlspring 19 pushing the first collar 20. As the carrier 7 moves withrespect to the chassis 2 during needle insertion the needle insertionmechanism 24 arrives in a state D illustrated in FIG. 12D. The arrowhead20.1 has moved with the carrier 7 and is still kept inwardly deflectedby the chassis 2 thus preventing the first collar 20 from disengagingthe carrier 7. The arrowhead 20.1 must be able to deflect in the outwarddirection O to allow retraction which will be discussed below. In orderto allow outward deflection the arrowhead 20.1 travels proximally beyondthe part of the chassis 2 shown in FIGS. 12A to 12F next to an aperture2.5 in the chassis 2. However, as long as the case 12 is being keptpressed against the injection site and not allowed to return in thedistal direction D beyond a predefined distance under load of thecontrol spring 19 the arrowhead 20.1 will be kept from deflecting in theoutward direction O by a first rib 12.3 on the case 12 (not illustratedin FIGS. 12A to F, see FIGS. 5A to 8A) during about the second half ofits motion for needle insertion.

The needle 4 is now fully inserted into the injection site asillustrated in FIGS. 6A and 6B. The time between the trigger button 13pressed and the needle 4 being fully inserted is very short, howeverseveral mechanical operations take place in this time. The needleinsertion depth is defined by the carrier 7 relative to the chassis 2not relative to the case 12, so if the user flinches or fails to holdthe auto-injector 1 hard against the skin, only the case 12 will move inthe distal direction D while the injection depth remains constant.

As soon as the plunger 9 has closed the gap to the stopper 6 under forceof the drive spring 8 the stopper 6 is pushed in the proximal directionP within the syringe 3 displacing the medicament M through the needle 4into the injection site.

Immediately prior to the end of injection with the stopper 6 havingalmost bottomed out in the syringe 3 as illustrated in FIGS. 7A and 7B anoise component 28 is released. The stack up of tolerances, most notablydue to the syringe 3 requires that the noise must always be releasedprior to the end of injection. Otherwise, with certain combinations ofparts, the noise would not always release. The noise component 28comprises an elongate portion 28.1 arranged within the distal plungersleeve 17 and a distal end plate 28.2 arranged between the carrier endface 10 and an end face of the trigger button 13. Two second resilientarms 30 originate from the distal carrier end face 10 and extend in theproximal direction P. A noise spring 29 is arranged to bias the noisecomponent 28 in the distal direction D relative to the carrier 7 byproximally bearing against a rib on the second resilient arms 30 anddistally against the noise component 28 (not illustrated).

Note: the noise component 28 is not illustrated in FIGS. 16A, B and Cfor clarity since it does not affect the function of the button releasemechanism 26. A noise release mechanism 31 for releasing the noisecomponent 28 is schematically illustrated in FIGS. 14A, 14B and 14C.Referring now to FIG. 14A, the noise release mechanism 31 comprises thesecond resilient arms 30. A ramped inward boss 30.1 is arranged on eachsecond resilient arm 30 which is engaged to a respective outwardeleventh ramp 28.3 on the elongate portion 28.1 of the noise component28 in such a manner that the second resilient arm 30 is deflected in theoutward direction O under load of the noise spring 29. In an initialstate A of the noise release mechanism 31 the second resilient arms 30are prevented from being outwardly deflected by outward support of thedistal plunger sleeve 17 thus preventing translation of the noisecomponent 28 relative to the carrier 7. The noise release mechanism 31remains in state A until immediately prior to the end of injection withthe stopper 6 having almost bottomed out in the syringe 3 as illustratedin FIGS. 7A and 7B. At this point the plunger 9 has been translated inthe proximal direction P relative to the carrier 7 to such an extentthat the second resilient arms 30 are no longer supported by the distalplunger sleeve 17. The noise release mechanism 31 has thus arrived in astate B illustrated in FIG. 14B. Due to the ramped engagement betweenthe ramped inward boss 30.1 and the outward eleventh ramp 28.3 thesecond resilient arm 30 is outwardly deflected under load of the noisespring 29 thus disengaging the noise component 28 from the carrier 7 andallowing the noise component 28 to move in the distal direction D drivenby the noise spring 29 in a state C illustrated in FIG. 14C. Hence, thenoise component 28 is accelerated in the distal direction D and thedistal end plate 28.2 impacts on the inside of the trigger button 13producing audible and tactile feedback to the user that the injection isabout finished.

FIGS. 8A and 8B show the auto-injector 1 with the stopper 6 havingentirely bottomed out in the syringe 3.

As mentioned above the user is able to let the case 12 move by a fewmillimetres in the distal direction D under the force of the controlspring 19 without affecting the position of the needle 4 as long as thatmotion is below a predefined distance. If the user wishes to end theinjection, at any time, they must allow the case 12 to move in thedistal direction D beyond that distance. FIGS. 9A and 9B show theauto-injector 1 lifted from the injection site with the case 12 movedall the way in the distal direction D so that the chassis 2 protrudesfrom the proximal end of the case 12. As the case 12 is moved the firstcollar 20 releases the carrier 7 and then the second collar 21 releasesfrom the case 12 and pulls the carrier 7 in the distal direction D. Thesequencing of this switching is critical as retraction will fail if bothcollars 20, 21 are attached to the carrier 7 at the same time. This isovercome by separating the switching of the collars 20, 21 by asignificant displacement of the case 12.

The switching of the first collar 20 is illustrated in FIGS. 12E and F.In FIG. 12E the case 12 has been allowed to move in the distal directionD under load of the control spring 19 during removal of theauto-injector 1 from the injection site. The first rib 12.3 (notillustrated, see FIG. 9A) is removed from outwardly behind the arrowhead20.1. The first collar 20 is still being pushed in the proximaldirection P by the control spring 19. Due to the engagement of theinward ninth ramp 20.3 on the arrowhead 20.1 with the distal tenth ramp7.6 on the carrier 7 the arrowhead 20.1 is deflected in the outwarddirection O into the aperture 2.5 of the chassis 2 (illustrated in FIGS.12A to 12F), the needle insertion control mechanism 24 arriving in astate E as illustrated in FIG. 12E, decoupling the first collar 20 fromthe carrier 7 and latching it to the chassis 2.

As the case 12 is moving further in the distal direction D on removalfrom the injection site the syringe retraction control mechanism 25switches from its state A (cf. FIG. 13A) into a state B illustrated inFIG. 13B. The case 12 and the second collar 21 locked to the case 12move together in the distal direction D while the carrier 7 is held inplace by the detent mechanism 18 in its state C as described above (cf.FIG. 11C). Due to this motion the inward boss 21.3 on the second beamhead 21.2 of the proximal beam 21.1 on the second collar 21 no longerinwardly abuts the carrier 7. Instead the inward boss 21.3 is deflectedin the inward direction I into a third recess 7.7 in the carrier 7 dueto the ramped engagement of the second beam head 21.1 to the rampedsecond case detent 12.2 under load of the control spring 19. The syringeretraction control mechanism 25 thus arrives in a state C as illustratedin FIG. 13C with the second collar 21 decoupled from the case 12 andcoupled to the carrier 7. The detent mechanism 18 applies a smallretarding force to the movement of the carrier 7 before the syringeretraction control mechanism 25 switches to state C as there is a smallsliding force, applied by the second collar 21, pulling the carrier 7 inthe distal direction D on translation of the case 12 in the distaldirection D when the needle insertion control mechanism 24 has alreadybeen switched into state E. If the carrier 7 moves too far in the distaldirection D before the second collar 21 switches, the case 12 runs outof travel before the inward boss 21.3 can deflect into the third recess7.7 preventing retraction.

Starting from the position C of the detent mechanism 18 (cf. FIG. 11C)the carrier 7 and hence the rhomboid ramp member 7.1 are translated inthe distal direction D under load of the control spring 19. Hence, thedistal fifth ramp 7.3 of the rhomboid ramp member 7.1 engages theproximal third ramp 2.3 on the first beam head 2.2 of the resilient beam2.1 in a manner deflecting the resilient beam 2.1 in the inwarddirection I. This applies the small retarding force to the movement ofthe carrier 7 required for ensuring the switching of the second collar21 to the carrier 7. The resilient beam 2.1 and the rhomboid ramp member7.1 are offset sideways to allow the resilient beam 2.1 to pass withoutcontacting the rhomboid ramp member 7.1 as soon as the first beam head2.2 is entirely inwardly from the ramp member 7.1 in a state Dillustrated in FIG. 11D.

The control spring 19 is grounded at its proximal end in the case by thefirst collar 20 being abutted against the chassis 2. The distal end ofthe control spring 19 moves the second collar 21 in the distal directionD taking with it the carrier 7 and hence the syringe 3 with the needle 4overcoming the detent mechanism 18 as illustrated in FIG. 11D. Note thatthe needle 4 is retracted out of the skin by the auto-injector 1 as soonas the user allows the case 12 to translate sufficiently far as opposedto auto-injectors with needle shields which require the user to removethe auto-injector from the injection site thereby themselves pulling theneedle out of the skin for allowing the needle shield to advance.

As the movement allowed of the noise component 28 is limited relative tothe carrier 7 it is no longer in contact with the trigger button 13which has moved in the distal direction D with the case 12 on removalfrom the injection site. When the retraction begins the noise spring 29does not provide any retarding force. Once the noise component 28 hitsthe trigger button 13 again on retraction of the carrier 7 the noisespring 29 must be recompressed, reducing the force driving the finalpart of retraction. In order to ensure a reliable retraction despitethis reducing force the control spring 19 must be appropriatelydimensioned.

The retraction ends when the distal collar 21 meets a first back stop12.4 on the case 12 as in FIGS. 10A and 10B. The arrowhead 20.1 on thefirst collar 20 is inwardly supported by the carrier 7 in a state Fillustrated in FIG. 12F and thus prevented from deflecting in the inwarddirection I. The outward sixth ramp 20.2 of the arrowhead 20.1 isengaged behind the first rib 12.3 on the case 12 preventing the case 12from being pushed in the proximal direction P again. A clearance may beprovided between the arrowhead 20.1 and the first rib 12.3 to allow fortolerances.

The detent mechanism 18 returns to state A as in FIG. 11A locking thecarrier 7 in position relative to the chassis 2 as it did initially,however it cannot be unlocked now as the case 12 cannot move relative tothe chassis 2.

A tab 20.4 on the first collar 20 is now visible through an indicatorwindow 32 in the case 12—indicating the auto-injector 1 has been used.

FIG. 17 is an isometric view of an alternative embodiment of the plungerrelease mechanism 27. The plunger release mechanism 27 prevents movementof the plunger 9 in the proximal direction P relative to the carrier 7until the carrier 7 is moved in the proximal direction P for needleinsertion. As opposed to the plunger release mechanism 27 of FIG. 15,where relative movement of the carrier 7 and trigger button 13 are usedto trigger the release of the plunger 9, the alternative embodiment ofFIG. 17 releases the plunger 9 by movement of the carrier 7 relative tothe second collar 21. FIG. 17 illustrates the plunger release mechanism27 prior to plunger release. The second collar 21 is shown transparentto improve clarity. The plunger 9 is being pushed in the proximaldirection P by the drive spring 8. In order for the plunger 9 toadvance, it must rotate around a twelfth ramp 7.8 on the carrier 7. Aramp member 9.1 on the plunger 9 is arranged to engage this twelfth ramp7.8. Rotation of the ramp member 9.1 is blocked by an inwardlongitudinal rib 21.5 on the second collar 21 splined in a longitudinalaperture 7.9 in the carrier 7. The case 12 and the second collar 21remain in the same position, i.e. coupled to each other for joint axialtranslation. On depression of the trigger button 13 the carrier 13 andthe plunger 9 being part of the drive sub-assembly are moved in theproximal direction P, first by the user pressing the trigger button 13and then by the control spring 19 taking over via the first collar 20 asdescribed above. Once the carrier 7 moves sufficiently far in theproximal direction P relative to the second collar 21 the ramp member9.1 on the collar 9 comes clear of the longitudinal rib 21.5 on thesecond collar 21 and can rotate past the proximal end of thelongitudinal rib 21.5 due to its ramped engagement to the twelfth ramp7.8 under load of the drive spring 8. Hence, the drive spring 8 advancesthe plunger 9 in the proximal direction P for injecting the medicamentM.

FIG. 18 is a longitudinal section of an alternative embodiment of thebutton release mechanism 26. Other than the button release mechanism 26of FIG. 16 which gives the appearance of a revealing trigger button 13on skin contact by switching the ground of the trigger button 13 betweenthe carrier 7 and the case 12, the button release mechanism 26 of FIG.18 starts with the trigger button 13 locked but protruding from thedistal end of the case 12. Once the carrier 7 has moved in the distaldirection D on skin contact of the chassis 2, it is possible to depressthe trigger button 13 and activate the auto-injector 1. This ensures asequenced operation.

In the embodiment of FIG. 18 the trigger button 13 has two proximalbeams 13.1, each of them having a ramped outward boss 13.4. In theinitial state shown in FIG. 18 the ramped outward bosses 13.4 areengaged in respective fourth recesses 12.5 in the case 12. Disengagingthe ramped outward bosses 13.4 from the fourth recesses 12.5 isprevented by the carrier 7 inwardly supporting the proximal beams 13.1in a manner to keep the proximal beams 13.1 from deflecting inwardly.Inward protrusions 13.5 on the proximal beams 13.1 abut against a secondrib 7.10 on the carrier 7 in a manner preventing the carrier 7 frommoving further in the proximal direction P in the initial state. Oncethe carrier 7 has moved in the distal direction D on skin contact of thechassis 2 a first window 7.11 in the carrier 7 is moved behind theinward protrusion 13.5 so as to allow the proximal beams 13.1 to beinwardly deflected due to their ramped engagement in the fourth recesses12.5 on depression of the trigger button 13. The proximal beams 13.1 arenow outwardly supported by the case 12 and remain engaged to the carrier7 even on retraction of the needle 4. The trigger button 13 doestherefore not return to its initial position, indicating that theauto-injector 1 has been used.

The button release mechanism 26 illustrated in FIG. 18 may preferably becombined with the plunger release mechanism 27 illustrated in FIG. 17.

FIGS. 19A and 19B show two longitudinal sections of an alternativeembodiment of the detent mechanism 18. The detent mechanism 18 of FIGS.11A to 11D, which may be referred to as a “race track” mechanism becauseof the first beam head 2.2 travelling around the rhomboid ramp member7.1 has multiple functions which control the movement of the carrier 7relative to the chassis 2. The alternative detent mechanism 18 of FIGS.19A and 19B uses three clips 7.12, 7.13, 2.6 to produce the same effect.

The first clip 7.12 is arranged as an outwardly biased resilient beam onthe carrier 7 extending from the carrier 7 in the proximal direction P.the first clip 7.12 is arranged to prevent the carrier 7 from beingmoved in the proximal direction P prior to the chassis 2 being depressedor rather the case 12 being translated on skin contact. The first clip7.12 is composed of two sections side by side. A first section 7.14prevents movement of the carrier 7 in the proximal direction P byabutting the chassis 2 in a recess. A second section 7.15 is arranged asan outwardly protruding clip head arranged to be ramped inwards by aramp feature 12.6 on the chassis 12 for releasing the first clip 7.12thereby unlocking the carrier 7 from the chassis 2 when the case 12 isbeing translated in the proximal direction P on skin contact. Alongitudinal slot 2.7 in the chassis 2 is arranged for allowing thesecond section 7.15 to slide in the proximal direction P once the lockhas been released. A slight friction force between the first clip 7.12and the chassis 2 provides the retarding force required to ensureretraction.

The second clip 7.13 is arranged as a resilient beam on the carrier 7extending in the distal direction D having an outwardly protruding thirdbeam head 7.16 with a proximal ramp. The third beam head 7.16 serves asa back stop against a third rib 2.9 on the chassis 2 for preventing thecarrier 7 moving in the distal direction D from its initial position.The carrier 7 and chassis 2 are assembled with the second clip 7.13 inthis position prior to inserting the syringe 3 into the carrier 7 whichis facilitated by the proximal ramp on the third beam head 7.16. Thesyringe 3 locks the clip in place by preventing inward deflection thuscreating a fixed stop.

The third clip 2.6 is a resilient beam on the chassis 2 extending in thedistal direction D. A ramped fourth beam head 2.8 on the third clip 2.6is arranged to inwardly engage in a fifth recess 7.17 in the carrier 7.Once the first clip 7.12 is unlocked, the user can load the third clip2.6 by pressing the carrier 7 in the proximal direction P on depressionof the trigger button 13. The third clip 2.6 is loaded in compression,i.e. it will bend outwards and release suddenly due to its rampedengagement to the carrier 7 providing the detent functionality similarto that illustrated in FIG. 11B.

FIG. 20 is a longitudinal section of a third embodiment of the detentmechanism 18 which is a variation on the embodiment of FIGS. 19A and19B. In this embodiment the detent function of the third clip 2.6 hasbeen added into the first clip 7.12. The lock between the case 12 andthe carrier 7 is released in the same way, but the detent is provided bydeflecting the first clip 7.12 inwards a second level which is achievedby the chassis 2 not having a slot 2.7 for the second section 7.15.Instead the second section 7.15, once ramped inwards by the ramp feature12.6 on the case 12 has to be further ramped inwards inside the chassis2 on axial load between the chassis 2 and the carrier 7, suddenlyreleasing their engagement.

FIG. 21 is a longitudinal section of an alternative embodiment of thenoise release mechanism 31. As opposed to the noise release mechanism 31of FIG. 14 where the noise spring 29 acts between the carrier 7 and thenoise component 28, in the embodiment illustrated in FIG. 21 the noisespring 29 acts between the case 12 and the noise component 28. Duringneedle insertion the noise spring 29 is compressed as the noisecomponent 28 moves with the carrier 7 relative to the case 12. When thenoise component 28 is released by the plunger 9 shortly before the endof dose, the noise component 28 moves in the distal direction D andimpacts the trigger button 13. Other than in FIG. 14 the noise spring 29is not being recompressed during needle retraction since it is groundedin the case 12 not in the carrier 7.

FIGS. 22A and 22B show longitudinal sections of an alternativeembodiment of the needle insertion control mechanism 24 which is alsoarranged to perform the detent function of the detent mechanism 18 onneedle retraction and needle insertion. FIG. 23 shows a correspondingisometric view. A fourth clip 20.5 on the first collar 20 is arranged asa resilient beam with a beam head having an inward proximal thirteenthramp 20.6 for engaging a fourth rib 7.18 on the carrier 7 and outwardlysupported by the case 12 so as to keep the first collar 20 engaged tothe carrier 7 prior to use, during needle insertion and duringinjection. When the user lifts the case 12 away from the injection siteat the end of injection or mid injection, a sixth recess 12.7 in thecase 12 is moved outwardly behind the fourth clip 20.5 allowing thefourth clip 20.5 to release when the carrier 7 is pulled in the distaldirection D by the second collar 21. Since the fourth clip 20.5 has tobe ramped outwards a small force is required to release the fourth clip20.5, providing the retraction detent.

A fifth clip 2.10 on the chassis 2 abuts a block 20.7 on the firstcollar 20 prior to use preventing the first collar 20 and hence thecarrier 7 engaged to the first collar 20 from moving in the proximaldirection P. In order to release, the fifth clip 2.10 must be deflectedoutwards and over the block 20.7. Outward deflection of the fifth clip2.10 is initially prevented by the case 12. Once the case 12 has movedon skin contact a second window 12.8 in the case 12 appears outwardlyfrom the fifth clip 2.10 allowing outward deflection. The fifth clip2.10 is then deflected by a fourteenth ramp 7.19 on the carrier 7 whenthe carrier 7 is pushed in the proximal direction P on button depressionas the fourth clip 20.5 does allow translation of the carrier 7 in theproximal direction P relative to the first collar 20 but not the otherway round. The detent for needle insertion is provided by having todeflect the fifth clip 2.10 when it is loaded by the control spring 19.

FIGS. 24A and 24B show longitudinal sections of a third embodiment ofthe needle insertion control mechanism 24, also arranged to perform thefunctions of the detent mechanism 18. FIG. 25 is an isometric view ofthe needle insertion control mechanism 24 of FIG. 24. The embodiment issimilar to that illustrated in FIGS. 22A, 22B and 23. The difference isthat the fifth clip 2.10 is arranged on the first collar 20 and theblock 20.7 is arranged on the chassis 2, i.e. their position has beenswitched, so there are two clips 2.10 and 20.5 on the first collar 20.

The fourth clip 20.5 is identical to that in FIG. 22B. It keeps thefirst collar 20 connected to the carrier 7 until the needle retractionis triggered, ensuring full injection depth is reached and maintaineduntil the retraction cycle is initiated by removing the auto-injector 1from the skin.

The fifth clip 2.10 provides the detent for needle insertion andreleases the first collar 20 from the chassis 2, initiating needleinsertion. The fifth clip 2.10 prevents the first collar 20 and hencethe carrier 7 engaged to the first collar 20 from moving in the proximaldirection P prior to use by abutting the block 20.7 on the chassis 2. Inorder to release, the fifth clip 2.10 must be deflected outwards andover the block 20.7. Outward deflection of the fifth clip 2.10 isinitially prevented by the case 12. Once the case 12 has moved on skincontact the second window 12.8 in the case 12 appears outwardly from thefifth clip 2.10 allowing outward deflection. The fifth clip 2.10 is thendeflected by the fourteenth ramp 7.19 on the carrier 7 when the carrier7 is pushed in the proximal direction P on button depression as thefourth clip 20.5 does allow translation of the carrier 7 in the proximaldirection P relative to the first collar 20 but not the other way round.The detent for needle insertion is provided by having to deflect thefifth clip 2.10 when it is loaded by the control spring 19.

FIGS. 26A and 26B show a longitudinal section of a third embodiment ofthe noise release mechanism 31. This embodiment works without the needfor a dedicated noise spring. The plunger 9 comprises a proximallyramped rib 9.2 arranged to splay two seventh clips 7.21 on the carrier 7immediately prior to the end of dose. When the proximally ramped rib 9.2has travelled past the seventh clips 7.21 they snap back and impact theplunger 9 generating a sound. The tubular shape of the carrier 7 helpsto transmit the sound. FIG. 26A shows the noise release mechanism 31before release. FIG. 26B shows the noise release mechanism 31 afterrelease. Proximal faces of the seventh clips 7.21 on the carrier 7 areaxially offset to facilitate assembly by lifting the seventh clips 7.21over the distal side of the proximally ramped rib 9.2 one by one.

FIGS. 27A and 27B show longitudinal sections of another embodiment ofthe auto-injector 1 in different section planes, the different sectionplanes approximately 90° rotated to each other, wherein theauto-injector 1 is in an initial state prior to starting an injection.The auto-injector 1 is essentially identical to the one described inFIGS. 1 to 16. However, other than the auto-injector of FIGS. 1 to 16the auto-injector 1 of this embodiment has a wrap-over sleeve triggerinstead of a trigger button.

The wrap-over sleeve trigger 12 is the same component as the case 12which has a closed distal end face 12.10 other than the one in FIGS. 1to 16. An internal trigger button 13 is arranged at the distal endinside the sleeve trigger 12. Other than in FIGS. 1 to 16 the triggerbutton 13 is not visible nor does it protrude from the case 12 in anystate. In the initial state a clearance 33 is provided between thedistal end face 12.10 of the sleeve trigger 12 and the internal triggerbutton 13 allowing for some travel of the sleeve trigger 12 withoutinterfering with the trigger button 13.

As the auto-injector 1 does not differ from the auto-injector of FIGS. 1to 16 in other respects it is essentially operated in the same way withthe following exceptions:

As the chassis 2 is placed against the injection site the sleeve trigger12 translates in the proximal direction P relative to the chassis 2 intothe advanced position in a first phase of sleeve travel removing theclearance 33 between the distal end face 12.10 of the sleeve trigger 12and the internal trigger button 13. As in the embodiment of FIGS. 1 to16 this motion unlocks the detent mechanism 18 and the trigger button13. As the user continues to depress the sleeve trigger 12 in a secondphase of sleeve travel thereby further advancing it in the proximaldirection P the distal end face 12.10 hits the internal trigger button13 thereby depressing it until the first collar 20 is released from thechassis 2 and the control spring force is coupled on to the carrier 7.The carrier 7 then advances until the internal trigger button 13 stopson another rib in the case 12 and the plunger release mechanism 27 isreleased (note the peg 14 is shorter in this embodiment.

From a user perspective, the detent mechanism 18 is arranged to providea resistive force when the user reaches the second phase of sleevetravel. Internally, there is no difference to the embodiment of FIGS. 1to 16 at this point.

Needle insertion is triggered by the user fully advancing the sleevetrigger 12 in the second phase of sleeve travel thereby fully depressingthe internal trigger button 13 and overcoming the detent mechanism as inthe embodiment of FIGS. 1 to 16.

As the control spring 19 takes over on button depression fully advancingthe carrier 7 for needle insertion the internal trigger button 13bottoms out on an internal fifth rib 12.11 in the sleeve trigger 12 andthe internal trigger button 13 switches back to being locked to thesleeve trigger 12 as in FIG. 16C.

The embodiment of FIGS. 27A and 27B may also be combined with thealternative features illustrated in FIGS. 17 to 26.

It goes without saying that in all ramped engagements between twocomponents described in the above embodiments there may be just one rampon one or the other component or there may be ramps on both componentswithout significantly influencing the effect of the ramped engagement.

1-14. (canceled)
 15. An auto-injector for administering a dose of aliquid medicament (M), comprising: a tubular chassis telescopable in anelongate chassis, a carrier subassembly comprising a tubular carrierslidably arranged partially inside the chassis and inside the case, thecarrier adapted to contain a syringe with a hollow injection needle, adrive spring and a plunger for forwarding load of the drive spring to astopper of the syringe, wherein the syringe is lockable for joint axialtranslation with the carrier, a control spring arranged around thecarrier, a needle insertion control mechanism for coupling a proximalend of the control spring to either the carrier for advancing it forneedle insertion or to the chassis, wherein the needle insertion controlmechanism comprises a first collar biased by the control spring in aproximal direction (P), wherein at least one fifth clip is arranged onone of the chassis or the first collar initially abutting a block on theother of the chassis or the first collar, wherein a ramped engagementbetween the fifth clip and the carrier is provided for outwardlydeflecting the fifth clip on translation of the carrier in the proximaldirection (P), wherein outward deflection of the fifth clip andtranslation of the carrier in the proximal direction (P) is initiallyprevented by the case outwardly abutting the fifth clip, wherein thecase is at least initially biased in the distal direction (D), whereinthe case is arranged to translate against the bias in the proximaldirection (P) relative to the chassis into an advanced position therebytranslating a second window in the case outwardly behind the fifth clipthus allowing outward deflection so as to decouple the fifth clip fromthe block and to allow the first collar to abut against the carrier andadvance it under load of the control spring.
 16. The auto-injectoraccording to claim 15, characterized in that the first collar comprisesa fourth clip for engaging a fourth rib on the carrier for needleinsertion, wherein at least one of the fourth clip and fourth rib isramped so as to outwardly deflect the fourth clip for disengaging thefourth clip from the fourth rib under load of the control spring,wherein outward deflection of the fourth clip is initially prevented bythe case, wherein the case is allowed to translate from the advancedposition in the distal direction (D) driven by the control spring whenthe auto-injector is lifted from the injection site thereby translatinga sixth recess in the case outwardly behind the fourth clip thusallowing outward deflection so as to decouple the first collar from thecarrier subsequently allowing the first collar to abut the chassis. 17.The auto-injector according to claim 15, characterized in: a triggerbutton arranged distally or laterally in or on the case, a plungerrelease mechanism arranged for releasing the plunger for injection whenthe carrier has at least almost reached an injection depth during needleinsertion, a syringe retraction control mechanism arranged for couplinga distal end of the control spring to either the carrier for needleretraction or to the case otherwise.
 18. The auto-injector according toclaim 17, characterized in that the plunger release mechanism comprisesat least one resilient arm on the carrier arranged to be in a rampedengagement to the plunger so as to disengage them under load of thedrive spring, wherein a peg protrudes from a distal end face of thetrigger button in the proximal direction (P) in a manner to support theresilient arm preventing disengagement of the carrier from the plungerand thus release of the drive spring when the carrier is in a distalposition, wherein the trigger button is arranged to remain in positionrelative to the case when the carrier is translated for advancing theneedle so as to pull the resilient arm away from the peg thus allowingdeflection of the resilient arm due to the ramped engagement under loadof the drive spring for disengaging the plunger from the carrier andreleasing the drive spring for drug delivery when the carrier hasreached a predefined position during needle advancement.
 19. Theauto-injector according to claim 17, characterized in that in theplunger release mechanism the plunger in an initial state is locked tothe carrier by a ramped engagement and by being prevented from rotatingout of this ramped engagement depending on a relative longitudinalposition of the carrier in the case, wherein the plunger is arranged tobe released for rotating out of the ramped engagement upon the needlereaching at least nearly a predefined injection depth on translation ofthe carrier in the proximal direction (P) for advancing the needlebeyond a proximal end of the auto-injector.
 20. The auto-injectoraccording to claim 19, characterized in that the carrier has alongitudinal aperture, wherein an outward protrusion is arranged on theplunger in a manner to engage a face on the carrier in the aperture,wherein at least one of the outward protrusion or the face on thecarrier is ramped so as to force the plunger to rotate when translated,wherein an inward longitudinal rib connected to the case inwardlyprotrudes into the longitudinal aperture in a manner to preventdisengagement of the outward protrusion from the face on the carrierprior to translation of the carrier for advancing the needle and whereinthe outward protrusion comes clear of the inward longitudinal rib ontranslation of the carrier for advancing the needle so as to rotate pasta proximal end of the inward longitudinal rib due to its rampedengagement to the carrier under load of the drive spring.
 21. Theauto-injector according to claim 20, characterized in that the inwardlongitudinal rib is arranged on a second collar arranged in the case andinitially locked to the case for joint axial translation, the secondcollar being part of a syringe retraction control mechanism, wherein thesyringe retraction control mechanism is arranged to disengage from thecase and engage to the carrier when the case is moved in the distaldirection (D) from a position with the needle in the injection depth,wherein a control spring is arranged in the case around the carrier, thecontrol spring acting between the second collar and a proximal firstcollar so as to bias the case or the carrier in the distal direction(D).
 22. The auto-injector according to claim 17, characterized in thatthe distally arranged trigger button is at least initially coupled tothe carrier, wherein the case is arranged to abut the trigger button inthe initial state preventing depression of the trigger button, whereinon translation of the case into the advanced position the trigger buttonremains coupled to the carrier thus emerging from the case so as toallow depression of the trigger button.
 23. The auto-injector accordingto claim 17, characterized in that the syringe retraction controlmechanism comprises a second collar bearing against the distal end ofthe control spring and having a resilient proximal beam with a secondbeam head having an inward boss, wherein the second beam head isarranged to be in a ramped engagement with a second case detent in thecase in a manner ramping the second beam head in the inward direction(I) under load of the control spring in the distal direction (D),wherein the inward boss is arranged to inwardly abut the carrier forpreventing inward deflection of the second beam head and keep the secondcollar locked to the case, wherein a third recess is arranged in thecarrier for allowing the inward boss to be inwardly deflected ontranslation of the case in the distal direction (D) relative to thecarrier.
 24. The auto-injector according to claim 17, characterized inthat the trigger button is arranged distally, wherein the case isarranged as a wrap-over sleeve trigger having a closed distal end facecovering the trigger button, wherein in an initial state a clearance isprovided between the distal end face of the sleeve trigger and thetrigger button allowing for some travel of the sleeve trigger againstthe bias of the control spring in the proximal direction (P) in a firstphase before abutting the trigger button.
 25. The auto-injectoraccording to claim 15, characterized in that a releasable noisecomponent is provided, capable of, upon release, generating an audibleand/or tactile feedback to a user, wherein the noise component isarranged to be released when the plunger reaches a position relative tothe syringe in which the stopper is located in proximity of a proximalend of the syringe, and wherein the released noise component impacts ona housing component.
 26. The auto-injector according to claim 25,characterized in that the housing component of the auto-injectorcomprises at least part of the chassis, the case, the trigger button,the carrier and/or the plunger.
 27. The auto-injector according claim15, characterized in that a visual use indicator is provided, comprisingat least one indicator window in the case, wherein a part of the chassisis arranged to be located behind the indicator window when the case isin its distal position biased by the control spring, wherein a tab onthe first collar is located outwardly from the part of the chassis afterthe collar has been translated in the proximal direction (P) duringneedle insertion, wherein the tab and the part of the chassis exhibit avisually distinctive feature.
 28. The auto-injector according to claim17, characterized in that the trigger button is initially coupled to thecase in a manner to protrude distally from the case and interlocked tothe chassis in a manner preventing the trigger button from disengagingthe case and thus preventing actuation of the trigger button in aninitial position, wherein the case is arranged to translate in theproximal direction (P) against the bias relative to the chassis when thechassis is pressed against an injection site thereby also translatingthe trigger button releasing the interlock to the chassis so as to allowactuation of the trigger button, wherein the trigger button is arrangedto lock in a more proximal position on actuation.